Functional Expression of IQGAP1 in Vasculature: Role in Reactive Oxygen Species‐dependent PDGF signaling and Vascular Migration

Abstract

Vascular smooth muscle cell (VSMC) migration in response to platelet-derived growth factor (PDGF) is a key event in atherosclerosis and restenosis. Reactive oxygen species (ROS) derived from Rac1-dependent NADPH oxidase play an important role in PDGF receptor (PDGFR) signaling linked to VSMC migration. We previously identified IQGAP1 as a novel VEGF receptor binding protein expressed in endothelial cells. IQGAP1 controls cellular motility by interacting with actin and active Rac1; however, its role in VSMC remains unknown. Here we show that IQGAP1 expression is significantly increased after PDGF stimulation. Overexpression of IQGAP1 using adenovirus (Ad.IQGAP1) enhances PDGF-stimulated autophosphorylation of PDGFR, Rac1 binding to IQGAP1, ROS production and VSMC migration. Moreover, IQGAP1 promotes tyrosine phosphorylation of PLCgamma without affecting ERK1/2 phosphorylation. IQGAP1 siRNA inhibits PDGF-stimulated ROS production and VSMC migration. Wound assays reveal that IQGAP1 accumulates at the leading edge where it colocalizes with F-actin in actively migrating VSMCs. IQGAP1 expression is dramatically increased in the neointima in ApoE knockout mice with high fat-diet and mice with wire injury. In summary, IQGAP1 functions as a PDGFR-binding scaffold protein to organize ROS-dependent PDGF signaling, thereby promoting VSMC migration, which may contributes to formation of neointima in response to vascular injury.